Understanding the Interactions of HighMobility Gr

Authors: Gauri Misra Shipra Gupta Neetu Jabalia

Publish Date: 2016/11/30

Volume: 10, Issue: 3, Pages: 476-485

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Abstract

Platinum coordination compounds having cis geometry are frequently prescribed for various types of cancers Protein dysregulation is one of the major factors contributing towards cancer metastasis Head and neck squamous cell carcinoma HNSCC is one of the cancers where platinumbased compounds are used either alone or in combination with radiation as therapy The underlying interactions of these compounds with both DNA and proteins are crucial for the drug response The compounds forms DNA adducts which are recognized by conserved nonchromosomal highmobility group box 1 HMGB1 proteins In the present study we report the molecular dynamics simulations with the aim of understanding the behavior of platinum molecules that bind DNA The binding pocket is identified using molecular docking approach The sixteen mer stretch of the DNA–dCC5IUCTCTGGACCTTCC  dGGAAGGTCCAGAGAGG duplex containing GG is the major adduct of the antitumor molecule We have performed comparison of inhibitory potential of the already known inhibitors of HNSCC against HMGB1binding pocket using simulations and docking Variations in the binding site are observed for these inhibitors–DNA–protein ternary complexes involving defined groups We have validated our results using geometrybased docking transformations against the specific binding site as well as blind docking that involves complete protein for the identification of specific binding site Effective dose of the compound reflects its activity The interactions between DNA and HMGB1 are defined by hydrogen bonds and van der Waals contacts However the ternary complex stabilization is mediated by hydrogen bonding and hydrophobic interactions Significant deviations are observed in the RMSD values We have classified the inhibitors in two categories where group A compounds shows interactions against the HMGB1 domain box B and group B toward both boxes A and B Experimental IC50 values corroborates with the binding energies of the compounds We propose the predicted pattern of binding as specific for platinum inhibitors These studies are a new addition to the existing structural–activity relationshipbased pharmacophore generation with a potential for use in the treatment of head and neck squamous cell carcinoma The compounds can be validated as lead molecules using in vitro and in vivo experimentsThe support of Department of Biotechnology Ministry of Science and Technology Government of India to Bioinformatics Centre at Biotech Park Lucknow is gratefully acknowledged We acknowledge the kind support of Dr Janardhan Reddy Research Associate Department of Microbiology and Molecular Biology National JALMA Institute of Leprosy and OMD Agra for technical review of the manuscript We would like to thank Department of Radiotherapy and Chemotherapy Chhatrapati Shahuji Maharaj Medical University Lucknow Uttar Pradesh India for useful discussions during the course of this work

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